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Lack of Tyrosine 320 Impairs Spontaneous Endocytosis and Enhances Release of HLA-B27 Molecules

Susana G. Santos^1,*,,, Antony N. Antoniou, Paula Sampaio^*, Simon J. Powis^,¶ and Fernando A. Arosa^2,*,

^* Institute for Molecular and Cell Biology, Porto, Portugal; Division of Cell Biology and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom; Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal; Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom; and ^¶ Bute Medical School, University of St. Andrews, St. Andrews, United Kingdom

Several lines of evidence suggest that endocytosis of MHC class I molecules requires conserved motifs within the cytoplasmic domain. In this study, we show, in the C58 rat thymoma cell line transfected with HLA-B27 molecules, that replacement of the highly conserved tyrosine (Tyr³²⁰) in the cytoplasmic domain of HLA-B27 does not hamper cell surface expression of ₂-microglobulin H chain heterodimers or formation of misfolded molecules. However, Tyr³²⁰ replacement markedly impairs spontaneous endocytosis of HLA-B27. Although wild-type molecules are mostly internalized via endosomal compartments, Tyr³²⁰-mutated molecules remain at the plasma membrane in which partial colocalization with endogenous transferrin receptors can be observed, also impairing their endocytosis. Finally, we show that Tyr³²⁰ substitution enhances release of cleaved forms of HLA-B27 from the cell surface. These studies show for the first time that Tyr³²⁰ is most likely part of a cytoplasmic sorting motif involved in spontaneous endocytosis and shedding of MHC class I molecules.

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